Inflammatory diseases affect more than fifty million Americans. As a result of basic research in molecular and cellular immunology over the last ten to fifteen years, approaches to diagnosing, treating and preventing these immunologically-based diseases has been dramatically altered. One example of this is the discovery of an inducible form of the cyclooxygenase enzyme. Constitutive cyclooxygenase (COX), first purified in 1976 and cloned in 1988, functions in the synthesis of prostaglandins (PGs) from arachidonic acid (AA). Three years after its purification, an inducible enzyme with COX activity was identified and given the name COX-2, while constitutive COX was termed COX-1.
COX-2 gene expression is under the control of pro-inflammatory cytokines and growth factors. Thus, the inference is that COX-2 functions in both inflammation and control of cell growth. While COX-2 is inducible in many tissues, it is present constitutively in the brain and spinal cord, where it may function in nerve transmission for pain and fever. The two isoforms of COX are nearly identical in structure but have important differences in substrate and inhibitor selectivity and in their intracellular locations. Protective PGs, which preserve the integrity of the stomach lining and maintain normal renal function in a compromised kidney, are synthesized by COX-1. On the other hand, PGs synthesized by COX-2 in immune cells are central to the inflammatory process. The discovery of COX-2 has made possible the design of new drugs and synergistic compositions that reduce inflammation without removing the protective PGs in the stomach and kidney made by COX-1.
Leukotriens and 5(s)-HETE are important mediators for inflammatory, allergic and obstructive process. Leukotriens increases micro vascular permeability and are potent chemo tactic agent. Inhibition of 5-lipoxygenase indirectly reduces the expression of TNF-α. 5-Lipoxygenase is therefore the target enzyme for identifying inhibitors, which have potential to cope with a variety of inflammation and hypersensitivity-based human diseases including asthma, arthritis, bowel diseases such as ulcerative colitis and circulatory disorders such as shock and ischemia.
Free radicals play a major role in the initiation and progression of a wide range of pathological diseases like cancer, Alzheimer's, Parkinson's and cardiovascular disease. In the food industry, free radicals have been found to be responsible in the deterioration of foods during processing and storage. In view of this, considerable attention has been given to the addition of antioxidants in foods and supplementation of antioxidants to biological systems to scavenge free radicals.
A yellow pigmented fraction isolated from the rhizomes of Curcuma longa contains curcuminoids belonging to the dicinnamoyl methane group. Curcuminoids are present to the extent of 3 to 5 percent in the raw material. They are considered the most important active ingredients and are believed to be responsible for the biological activity of Curcuma longa. Though their major activity is anti-inflammatory, curcuminoids have been reported to possess antioxidant, antiallergic, wound healing, antispasmodic, antibacterial, antifungal, antitumor and antiHIV activity as well. Curcumin was isolated in 1815 and structurally defined in 1910. Other major curcuminoids isolated from Curcuma longa include demethoxycurcumin and bisdemethoxycurcumin. Curcuminoids may be found in other botanicals in addition to Curcuma longa, such as Curcuma xanthorrhiza and Curcuma zedoaria. Curcuminoids are well known for their anti-inflammatory activity. Turmeric is one of the oldest anti-inflammatory drugs used in Ayurvedic medicine.
The pharmacokinetics involving the safety, toxicity, dose range and biological properties of turmeric and its components, including curcumin is known, and the turmeric is readily available in various food stores.
The anti-inflammatory properties of curcumin were shown to inhibit the 5-lipoxygenase activity in rat peritoneal neutrophils as well as the 12-lipoxygenase and the cyclooxygenase activities in human platelets (Ammon, H. P. T. et al., J. Ethopharmacol., 1993, 38, 113-119). Curcumin had no significant effect on quercetin-induced nuclear DNA damage, lipid peroxidation and protein degradation and thus has the unique potential of acting as both pro- and antioxidants, depending on the redox state of their biological environment (Saura, C. et al., Cancer Letters, 1992, 63, 237-241).
Among the bibliographic references of the most interesting patents existing in the data banks, application FR2,655,054 about the cellular protection agents contained in curcuminoids obtained from Curcuma longa, ascorbic acid and/or dismutase super oxide (DSO) stands out. Curcuminoids have a known antioxidizing effect, as well as ascorbic acid and DSO that carry out a synergic effect.
The gum resin of the plant Boswellia serrata (Burseraceae) has long been in use for the treatment of rheumatoid arthritis and gout by the practitioners of Ayurvedic medicines in the Indian system of medicine. Various extracts of the gum resin have shown potent anti-inflammatory and anti-arthritic activity in laboratory animals, as well as during clinical trials (Atal, C. K. et al., Ind. J. Pharm., 1980, 12, 59; Pachnanda, V. K. et al., Ind. J. Pharm., 1981, 13, 63). In a detailed pharmacological study, Singh et al have established that the alcoholic extract of B. serrata gum resin displayed marked anti-inflammatory activity in carrageenan induced edema in rats and mice and dextran oedema in rats (Singh, G. B. et al., Agents and Action, 1986, 18, 407). It has also been recognized in the past that the ethanolic extract of the gum resin of B. serrata inhibits the formation of Leukotriene B4 in rat peritoneal neurophils. Leukotriene B4 is one of the important mediators of inflammatory reactions (Ammon, H. P. T. et al., Planta Medica, 1991, 57, 203).
A composition of enriched demethylated curcuminoids, enriched 3-O-acetyl-11-keto-β-boswellic acid (AKBA) and optionally other ingredients for preserving the health of joint tissues, for treating arthritis or other inflammatory conditions with COX-2 and 5-LOX specificity has not yet been discovered. A composition comprising demethylated curcuminoids, AKBA and optionally other ingredients to synergistically inhibit COX-2 and 5-LOX with high specificity and support the normalization of joint function has also not yet been discovered.
An important need therefore exists for dietary composition suitable for human patients that are synergistic in that they have stronger effects than the sum of the effects of the individual components and also synergistic with standard clinical treatment of inflammatory conditions and in the prior art, there is no such synergistic 5-lipoxygenase inhibitory composition for inflammatory diseases.
It is therefore an objective of the present invention to provide a non-toxic dietary supplement composition, which prevents or cure 5-lipoxygenase mediated disorders like inflammatory diseases (e.g. rheumatoid arthritis, osteoarthritis, and periodontal disease), asthama, and bowel disease such as ulcerative colitis and circulatory disorders such as shock and ischemia
It is a further objective of the present invention to provide a composition for preventing free radical mediated disorders such as cancer, Alzheimer's, Parkinson's and cardiovascular disease.
Thus, it would be useful to identify an enriched natural composition that would specifically inhibit or prevent the synthesis of COX-2 and 5-LOX. Such a composition, containing enriched demethylated curcuminoids, enriched AKBA, which would be useful for preserving the health of joint tissues, for treating arthritis or other inflammatory conditions, asthma, bowel disease such as ulcerative colitis and circulatory disorders such as shock and ischemia has not previously been discovered.
U.S. Pat. No. 6,521,271 described the methods of promoting improvement of skin condition by administering a turmeric component and glycolic acid to a patient afflicted with a skin disorder.
U.S. Pat. No. 6,264,995 described an herbal composition for reducing inflammation in bones and joints by inhibiting the enzyme cyclooxygenase-2. This composition is prepared from holy basil; turmeric, ginger, green tea, rosemary, huzhang, Chinese goldthread, barberry, oregano and scutellariae baicalensis.
U.S. Pat. No. 6,841,177 disclosed antiproliferative and photosensitization activities of Curcuma longa extract and its use in proliferative diseases such as psoriasis, as reducers of plasmatic fibrinogen and the Apolipoprotein B/Apolipoprotein A-1 quotient, without altering other coagulation parameters.
U.S. Pat. No. 6,440,468 disclosed a method for obtaining apolar and polar extracts of Curcuma and applications thereof. A process for obtaining the apolar extract comprises: (a) extracting the rhizomes with an organic solvent; (b) filtration and evaporation to dryness of the extract; (c) dissolution of the oleoresin obtained in hot conditions, precipitation while allowing to cool down and filtration of the solid; (d) drying and recrystallizing the solid in order to obtain a product having a purity in curcuminoids higher than 90%. A process for obtaining the polar extract comprises: (i) extraction of the rhizomes with water at 50-70° C. and (ii) filtration and evaporation of the water. Application of the compositions and preparations as catchers of free radicals and anti-ageing agents, as well as reducing agents to reduce the plasma levels of lipid peroxides in human beings are disclosed.
U.S. Pat. No. 5,494,668 disclosed a method of treating degenerative musculoskeletal diseases such as rheumatoid arthritis and osteoarthritis in an animal, typically a human, comprises administering to the animal, typically in a convenient dosage form, a therapeutically effective amount of the beneficiated extracts of the plants ashwagandha (Withania somnifera), sallai guggul (Boswellia serrata), turmeric (Curcuma longa), and ginger (Zingiber officinale) in a predetermined proportion relative to each other with or without other biologically active inorganic ingredients, such as zinc sulphate. The beneficiated plant extracts are made in accordance with a novel process which is also disclosed.
U.S. Pat. No. 5,629,351 disclosed a novel fraction comprising a mixture of boswellic acids, wherein the fraction exhibits anti-inflammatory and antiulcerogenic activities. Also disclosed is a novel boswellic acid compound exhibiting anti-inflammatory, antiarthritic and antiulcerogenic activities. Also disclosed is a process for isolating a boswellic acid fraction and individual boswellic acids therefrom.
US Patent Application 20030152585A1 disclosed herbal composition comprising a mixture of herbs such as Tinospora cordifolia, Aloe Vera, Curcuma longa, Withania somnifera, Achyranthus asperea, Ocimum sanctum and Picorrhiza kurroa for treatment of hematological malignancies.
U.S. Pat. No. 6,979,470 disclosed curcuminoid compositions comprising an effective amount of a curcuminoid species and an effective amount of a diterpene lactone species, a triterpene species or derivatives thereof that have a synergistic effect on specific inhibition of inducible COX-2 activity and have minimal effect on COX-1 activity.
US Patent Application 20040247700A1 disclosed curcuminoid compositions exhibiting synergistic inhibition of the expression and/or activity of cyclooxygenase-2 and this composition is useful for treating e.g. inflammation or arthritis, comprising curcuminoid and diterpene lactone or triterpene, and specifically inhibits inducible cyclooxygenase-2 (COX-2) activity.
US Patent Application 20030096027A1 and 20050129791A1 disclosed curcuminoid compositions exhibiting synergistic inhibition of the expression and/or activity of cyclooxygenase. It is also disclosed this composition for treating e.g. inflammation or inflammation based diseases, comprising curcuminoid species and alpha-acid (hops plant products) or beta-acid (lupulones).
US Patent Application 20030108628A1 described curcuminoid compositions, which exhibits synergistic inhibition of the expression and/or activity of cyclooxygenase. It also disclosed this composition for treating e.g. inflammation or arthritis, comprising curcuminoid and diterpene lactone or triterpene, and specifically inhibits inducible cyclooxygenase-2 (COX-2) activity.
US Patent Application 20050191375A1 described synergistic anti-inflammatory pharmaceutical compositions and related methods using curcuminoids or methylxanthines. It also disclosed the composition for reducing inflammation or treating e.g. pain, cancer, rheumatoid arthritis, psoriasis, ulcerative colitis and conjunctivitis comprises fraction isolated or derived from hops and methylxanthine.
US Patent Application 20050123632A1 described anti-inflammatory activity of a specific turmeric extract. It also disclosed mixture of turmeric oils for pharmaceutical or nutraceutical composition for treating inflammation e.g. rheumatoid arthritis, comprises hexane soluble fraction.
US Patent Application 20030216600A1 described novel polyhydroxy curcumins having antioxidant activity and these new polyhydroxycurcumins are useful as antioxidants.
European Patent 1133992A1 described novel pharmacological activities of Curcuma longa extracts. The use of aqueous alcoholic extract of Curcuma longa in composition having e.g. photosensitizing, antiproliferative and fibrinogen level reducing activity, used e.g. for treating psoriasis is also disclosed.
The patent WO03007975A1 described curcuminoid compositions, which exhibits synergistic inhibition of the expression and/or activity of cyclooxygenase-2. It also disclosed the composition useful for treating e.g. inflammation or arthritis, comprising curcuminoid and diterpene lactone or triterpene, and specifically inhibits inducible cyclooxygenase-2 (COX-2) activity.
The patent WO06062681A1 described curcuminoid compositions exhibiting synergistic inhibition of the expression and/or activity of cyclooxygenase-2. The formulation comprises, as a first component an effective amount of a curcuminoid species and an effective amount of a second component selected from the group consisting of an alpha-acid species (hops plant products) or beta-acid species (lupulones) or derivatives thereof.
The patent WO05084230A2 described synergistic anti-inflammatory pharmaceutical compositions and related methods using curcuminoids or methylxanthines. The composition useful for reducing inflammation or treating e.g. pain, cancer, rheumatoid arthritis, psoriasis, ulcerative colitis and conjunctivitis comprises fraction isolated or derived from hops and methylxanthine is disclosed.
The patent GB2388539A1 disclosed two polyherbal formulations for treating cancer, comprises mixture of six or four herbs, or mixture of active ingredients extracted or synthesized from herbs. The first formulation comprises a mixture of Glycine max, Lycopersicon esculentum, Allium sativum, Curcuma longa, Linum usitatissimum and Convolvulus arvensis. The second formulation comprises a mixture of Tinospora cordifolia, Withania somnifera, Phyllanthus emblica and Asparagus racemosus. 
U.S. Pat. No. 5,629,351 described boswellic acid compositions and preparation thereof. The composition comprises a new fraction containing known boswellic acids and new 2-alpha, 3-alpha-dihydroxy urs-12-en-24-oic acid is useful as synergistic anti-inflammatory, antiarthritic and antiulcerogenic agent.
The patent AU0075253A5 described novel pharmacological activities of Curcuma longa extracts. The use of aqueous alcoholic extract of Curcuma longa in composition having e.g. photosensitizing, antiproliferative and fibrinogen level reducing activity, used e.g. for treating psoriasis is also disclosed.
US patent application 20040166178A1 described 3-O-acetyl-11-keto-boswellic acid or its extract in a topical composition for treatment and prevention of lines and to relax the skin.
The patent also disclosed the use of composition comprising Boswellia serrata extract for topical application to the skin, as an agent to soften lines and/or relax the skin.
The patent WO0057893A1 disclosed the composition comprises an extract of Boswellia plant and carrier for use on hair and skin for reducing irritation.
The patent WO0062751A2 disclosed the composition comprises Boswellia plant extract, carrier and flavor ingredient for treating irritation or inflammation in mouth.
The patent WO03077860A2 disclosed boswellia composition comprises an enriched 3-β-acetyl-11-keto-β-boswellic acid (AKBA) for treating e.g. inflammation. It also disclosed a manufacturing process by peracetylating a boswellia serrata pentacyclic terpene acidic fraction extract to provide 3-beta-acetoxy-11-keto-beta-boswellic acid.
The patent IN0182615A described a process for the isolation of a new boswellic acid from the gum resin of the plant boswellia serrata. It also disclosed the composition for use on hair and skin for reducing irritation comprises extract of Boswellia plant and carrier.
U.S. Pat. No. 6,589,516 described compositions containing Boswellia extracts. The Composition for use on hair and skin for reducing irritation comprises extract of Boswellia plant and carrier is also disclosed.
Thus none of the prior art mentioned above relates to a composition comprising enriched AKBA extracts and enriched demethylated curcuminoids show synergistic 5-lipoxygenase inhibition.
It is therefore an object of the present invention to provide a non-toxic dietary supplement composition, which prevents or cure COX-2 and 5-lipoxygenase mediated disorders, inflammatory diseases like rheumatoid arthritis, periodontal disease, asthma, bowel disease such as ulcerative colitis and circulatory disorders such as shock and ischemia, free radical mediated disorders such as cancer, Alzheimer's, Parkinson's and cardiovascular disease.